Molecular signatures of hyperexcitability and lithium responsiveness in bipolar disorder patient neurons provide alternative therapeutic strategies.

Bipolar disorder (BD) is a multifactorial psychiatric illness affecting about 1% of the world population. The first line treatment, lithium (Li), is effective in only a subset of patients and its mechanism of action remains largely elusive. In the present study, we used iPSC-derived neurons from BD patients responsive (LR) or not (LNR) to lithium and combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics to report mechanistic insights into neuronal hyperactivity in BD, and Lis mode of action. We show a selective rescue of neuronal hyperactivity by Li in BD LR neurons through changes in Na+ currents. The whole transcriptome sequencing revealed altered gene expression in BD neurons in pathways related to glutamatergic transmission, and Li selectively altered those involved in cell signaling and ion transport/channel activity. We found the therapeutic effect of Li in BD LR patients was associated with Akt signaling and confirmed that an Akt activator mimics Li effect in BD LR neurons. Further, we showed that AMP-activated protein kinase (AMPK) reduces neural network activity and sodium currents in BD LNR patients. These findings suggest the potential for novel treatment strategies in BD, such as Akt activators in BD LR cases, and the use of AMPK activators for BD LNR patients.